Alzheimer's disease (AD) and its related dementias (ADRD) are neurodegenerative diseases that cause a significantly public health problem. A recent survey reports that an estimated 5.4 million Americans have AD in 2016 and by mid-century, the number of people living with AD in the United States is projected to grow to 13.8 million. While the prevalence of AD continues to increase substantially, particularly with a rise in aging population, successful approaches for preventing and treating AD remains elusive. No medications are available today to stop or reverse AD progression. Clearly, early diagnosis and early prevention/intervention are important strategies for tackling the development of AD. Multiple factors including both genetic and environmental factors have been implicated in the development of AD. Among them, growing evidence has suggested the association between metabolic disorder/type 2 diabetes and AD; dysfunctions of insulin and glucose metabolism are linked to brain cognitive impairment and mild cognitive impairment (MCI) is often an early sign of AD. Because of the complexity of AD progression, however, the critical molecular and cellular mechanisms of insulin and/or glucose in AD have yet to be established. In the past, we have used rodent models to identify an important role for the orexigenic neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) in the regulation of energy balance and glucose homeostasis. Overexpression of NPY in the DMH of OLETF rats contributes to their hyperphagia, obesity and impaired glucose tolerance, whereas knockdown of NPY in the DMH ameliorates these alterations. We have further revealed an important role for DMH NPY in thermoregulation; DMH NPY knockdown promotes brown adipocyte development in white adipose tissue (WAT) and increases both brown adipose tissue (BAT) and browning WAT thermogenesis. This project is aimed at exploring a potential role for manipulation of DMH NPY signaling to modulate energy metabolism to intervene aging and AD. The results from this project will allow us to develop an additional focus of AD-related metabolic research, leading to a potential strategy for preventing and treating AD and ADRD. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page